Mini-Symposium - Inhaled Corticosteroids Safety Panel
Inhaled corticosteroids: Effects on growth and bone health

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Abstract

Background

Both slowed growth in children and reduced bone mineral density (BMD) are systemic effects of corticosteroids, and there is concern about the degree to which these systemic effects affect growth and BMD.

Objective

To engage in a data-driven discussion of the effects of inhaled corticosteroids (ICSs) on growth in children and BMD.

Methods

Articles were selected based on their relevance to this review.

Results

Studies of ICSs in children in which growth was a secondary outcome have revealed slowed growth associated with low doses of budesonide, fluticasone propionate, and beclomethasone dipropionate. In the study of budesonide, the effect was permanent, and in the study of fluticasone propionate, the effect was long-lasting, but it is unclear whether the effect was permanent. However, the results of studies in which growth was the primary outcome were mixed. Slowed growth was detected in a study of beclomethasone dipropionate; however, slowed growth was not detected in a study of ciclesonide or flunisolide. A decrease in BMD acquisition in children was associated with high doses but not low to medium doses of ICSs. In adults, there was a dose-related effect of ICSs on BMD. Both higher daily dose and larger cumulative dose were associated with increased bone density loss.

Conclusion

Because of the systemic effects on growth and bone health, children should be monitored for growth using stadiometry every 3 to 6 months and BMD should be monitored yearly in patients being treated with high doses of ICSs.

Introduction

Slowed growth and reduction in bone mineral density (BMD) are known adverse effects of systemic exposure to corticosteroids. Studies have found systemic effects of oral corticosteroids on growth,[1], [2], [3] BMD,4 and risk of fracture.5 Systemic exposure is reduced when corticosteroids are inhaled instead of taken orally or parenterally. However, although asthma treatment and management guidelines recommend inhaled corticosteroids (ICSs) as the preferred first-line therapy for asthma,[6], [7] uncertainty remains among some clinicians about the extent of systemic effects among ICSs. In this article, we discuss the data on ICS systemic effects on growth and bone health.

The effects of ICSs on growth in children and bone health have been extensively reviewed in the past, and several recent reviews[8], [9], [10], [11] summarize this area very well. However, some clinicians who do not treat patients with asthma on a regular basis, for example, practitioners in primary care or pediatrics, are uncertain of the balance between ICS efficacy and safety. This article is one in a series of articles in a minisymposium entitled Inhaled Corticosteroids in Asthma: The Balance Between Safety and Efficacy, which was developed to help guide clinicians through identified knowledge and practice gaps concerning the balance of ICS efficacy and safety, the effects of ICS delivery and devices, and the importance of patient education and effective communication. As such, the goal of this article is not to comprehensively review all growth and bone health studies but to highlight key articles for clinicians who might not be familiar with the literature. This article focuses on key, well-designed studies of particular populations of interest. In particular, this review focuses on well-designed growth studies funded by the National Institutes of Health (NIH) and pharmaceutical industry after issuance of guidance by the US Food and Drug Administration (FDA).

Systemic availability varies among ICSs and depends on an ICS's pharmacokinetics, formulation, and delivery.11 These effects are discussed in more detail in 2 other articles in this minisymposium (Inhaled Corticosteroids: Ocular Safety and The HPA Axis and Inhalation Devices, Delivery Systems, and Patient Technique). Factors such as receptor-binding affinity, lipid conjugation, protein binding, and clearance from systemic circulation contribute to systemic adverse effects.11 In addition, drug formulation can affect the proportion of the ICS dose that is delivered to the lungs and systemic availability. In particular, in pressurized metered-dose inhalers (pMDIs), hydrofluoroalkane solution formulations deliver a higher fraction of smaller particles to the distal airways and distribute the drug more evenly throughout the lungs compared with chlorofluorocarbon formulations.12 The type of device can also affect systemic availability. Evidence suggests that compared with dry powder inhalers (DPIs), pMDIs may enhance lung deposition while reducing systemic bioavailability via the gastrointestinal tract.[13], [14] Note that the major source of systemic bioavailability of ICSs is the lung and not the gastrointestinal tract.15 In addition, ICS bioavailability is affected by the choice of spacers and masks.[16], [17] Nebulizers also affect bioavailability, as shown in one of the few growth studies in which an ICS was delivered by nebulizer.18

Section snippets

Growth in Children

A frequently expressed concern of ICSs is the systemic effects on growth in children. Growth is considered the most sensitive indicator of systemic corticosteroid activity by the FDA—more sensitive than the hypothalamic-pituitary-adrenal axis.19 However, detecting effects on growth is confounded by growth rates that vary throughout childhood. Our focus is on high-quality, well-designed studies with treatment durations of approximately 1 year or longer. These include NIH-funded studies that

Bone Health

ICSs also have systemic effects on bone health. Glucocorticoids cause reduced bone formation and increased bone resorption, which in turn decrease bone mass.33 Bone mass increases during childhood, peaking between 20 and 40 years of age.34 After the age of approximately 30 years, bone mass gradually decreases. Corticosteroid use can affect both the increase in bone mass in children and the rate of bone mass loss in adults. For adults, the main concerns of corticosteroid use are osteoporosis and

Conclusions

Low doses of systemically active ICSs can suppress growth and permanently affect the adult height of children with mild or moderate persistent asthma. The effect on adult height is on the order of 1 to 1.5 cm. Although this effect on growth should not stop us from using ICSs for asthma, it should be part of shared decision making among the child, the parent, and the physician. ICSs differ in their levels of systemic activity, and some ICSs, even at the highest recommended dose, have no

Acknowledgments

Thanks to Dr Rohit Katial for organizing the discussion panel and the panelists for their invigorating discussion and to Elise Eller, PhD, for her assistance in preparing this article. The National Jewish Health Office of Professional Education, particularly Matthew Stern and Andrea Harshman, MHA, CHCP, were instrumental in the development of this article.

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    Disclosures: Dr Skoner declares that he has received grant and research support from Genentech, GlaxoSmithKline, Greer, Merck, Novartis, Sunovion, and Teva. Dr Skoner is a consultant for Greer, Meda, Merck, Mylan, Sunovion, and Teva. He also states that he is on a speaker's bureau for Greer, Genentech, Meda, Merck, Novartis, and Sunovion.

    Funding Sources: This article was supported by an independent educational grant from Meda Pharmaceuticals Inc.

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